Stereoisomers are molecules which possess identical chemical formulas with the same atoms bonded to one another, but differ in the manner in which these atoms are arranged in three-dimensional space. While the structural differences between stereoisomers are subtle and of little consequence in some chemical reactions, they can be very important in compounds utilized in biological systems, such as agricultural chemicals, drugs and other biologically active compounds, and in intermediates used to prepare these compounds.
Synthesis of these biologically-active compounds by techniques which produce racemic intermediate mixtures frequently result in compounds with lower specific bioactivity due to the presence of undesired stereoisomers which are biologically or functionally inactive.
A chemical reaction is said to be stereoselective if one set of stereoisomers is formed exclusively or predominantly. It can be commercially important to stereoselectively synthesize the desired isomer of an intermediate in the production of some biologically active compounds. The use of stereoselective reactions in the manufacture of such biologically-active compounds can also help minimize waste and disposal problems associated with the production of unwanted isomeric byproducts.
U.S. Pat. Nos. 3,249,499 and 3,393,202 describe the preparation of certain 5,6-dihydro-1,4-oxathiin compounds without the use of an intermediate 1,3-oxathiolane sulfoxide. The preparation methods described therein involve the use of chlorinating agents.
In an alternative method for the production of 5,6-dihyro-1,4-oxathiin compounds, one of the intermediates is a 1,3 oxathiolane sulfoxide which is stereospecific, i.e., it can exist in a "cis" or "trans" configuration. It is known to those skilled in the art that the cis stereoisomers of certain 1,3 oxathiolane sulfoxides lead to a higher yields of the desired oxathiin product. Both of the "cis" and "trans" sulfoxide stereoisomers are products of the oxidation of 1,3-oxathiolane. See, for example, Lee et al., J. Org. Chem. 51, 2789-2795 (1986).
A method of synthesis of 5,6-dihydro-1,4-oxathiin compounds which utilizes a 1,3-oxathiolane sulfoxide as an intermediate, is described in U.S. Pat. Nos. 4,152,334; 4,182,716; and 4,247,707, which essentially consists of oxidizing a 1,3-oxathiolane in the presence of hydrogen peroxide to produce a 1,3-oxathiolane sulfoxide intermediate as a mixture of the two possible stereoisomers, and then subjecting the 1,3-oxathiolane sulfoxide intermediate to acid-catalyzed rearrangement to form the desired oxathiin carboxanilide.
In the rearrangement of mixtures of the cis and trans isomers of 1,3-oxathiolane sulfoxide intermediate, unwanted byproducts are formed in amounts proportional to the amount of trans stereoisomer present in the mixture. It would be desirable, therefore, to maximize the yield of the cis stereoisomer of the 1,3-oxathiolane sulfoxide intermediate and minimize the yield of trans stereoisomer, during the oxidation step.
Methods for stereoselective synthesis of 1,3-oxathiolane sulfoxides have been previously described. Lee et al, supra, report that oxidation of 2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide with hydrogen peroxide in acetic acid produces a 70:30 mixture of the cis stereoisomer to the trans stereoisomer, whereas similar oxidation with 85% m-chloroperbenzoic acid produces an 85:15 cis: trans mixture.
Lee and Park, Taehan Hwahakhoe Chi 31, 197-202 (1987); Chemical Abstracts 108, 5888d (1988) describe the use of a combination of aqueous hydrogen peroxide and benzeneseleninic acid at -5.degree. to 0.degree. C. to prepare a mixture of sulfoxides with a cis:tran stereoisomer ratio of 93:7.
However, the procedure in Lee and Park supra, is not suitable for commercial production. Quantitative overoxidation of the sulfoxides to give sulfones resulting from the the presence of excess aqueous hydrogen peroxide and benzeneseleninic acid, can be a major undesirable side reaction. See, for example, Reich et al., Synthesis, 299-301 (1978). Overoxidation can only be avoided by carefully controlling the activity of the oxidant in the reaction, requiring either very low temperatures and/or very slow addition rates of the oxidant to moderate the rate of reaction and avoid the presence of excess oxidant at any given time. Such low temperatures and very slow rates of addition are cumbersome to achieve and maintain, and are, therefore, not amenable to large-scale production.
It is an object of this invention to provide a new method for the preparation of 1,3-oxathiolane sulfoxide compounds. In particular, it is an object of this invention to provide a novel process for the stereoselective preparation of the cis-stereoisomer of 1,3-oxathiolane sulfoxide compounds which is commercially useful. It is a further object to provide a novel process for the preparation of 5,6-dihydro-1,4-oxathiin compounds.